8-azabicyclo[3.2.1]oct-2-ene and -octane derivatives

ABSTRACT

The present invention relates to novel 8-azabicyclo[3.2.1]oct-2-ene and -octane derivatives which are found to be cholinergic ligands at the nicotinic Acetyl Choline Receptors. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of chemical substances.

This application is a Continuation of PCT International Application No.PCT/DK99/00661 filed on Nov. 26, 1999, which was published in Englishand which designated the United States, and on which priority is claimedunder 35 U.S.C. §120, the entire contents of which are herebyincorporated by reference.

TECHNICAL FIELD

The present invention relates to novel 8-azabicyclo[3.2.1]oct-2-ene and-octane derivatives which are found to be cholinergic ligands at thenicotinic Acetyl Choline Receptors.

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or disorders as diverse as thoserelated to the cholinergic system of the central nervous system (CNS),diseases or disorders related to smooth muscle contraction, endocrinediseases or disorders, diseases or disorders related toneurodegeneration, diseases or disorders related to inflammation, pain,and withdrawal symptoms caused by the termination of abuse of chemicalsubstances.

BACKGROUND ART

The endogenous cholinergic neurotransmitter, acetylcholine, exert itsbiological effect via two types of cholinergic receptors, the muscarinicAcetyl Choline Receptors (mAChR) and the nicotinic Acetyl CholineReceptors (nAChR).

As it is well established that muscarinic ACh receptors dominatequantitatively over nicotinic ACh receptors in the brain area importantto memory and cognition, and much research aimed at the development ofagents for the treatment of memory related disorders have focused on thesynthesis of muscarinic ACh receptor modulators.

Recently, however, an interest in the development of nicotinic AChreceptor modulators has emerged. Several diseases are associated withdegeneration of the cholinergic system i.e. senile dementia of theAlzheimer type, vascular dementia and cognitive impairment due to theorganic brain damage disease related directly to alcoholism. Indeedseveral CNS disorders can be attributed to a cholinergic deficiency, adopaminergic deficiency, an adrenergic deficiency or a serotonergicdeficiency.

The present invention is devoted to the provision novel nicotinicreceptor modulators useful for therapy or diagnosis, which modulatorsare structurally close analogues of the compounds described in WO98/54181 (NeuroSearch A/S).

SUMMARY OF THE INVENTION

The present invention is devoted to the provision novel nicotinicreceptor modulators, which modulators are useful for the treatment ofdiseases or disorders related to the cholinergic receptors, and inparticular the nicotinic ACh receptor (nAChR).

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or disorders as diverse as thoserelated to the cholinergic system of the central nervous system (CNS),diseases or disorders related to smooth muscle contraction, endocrinediseases or disorders, diseases or disorders related toneurodegeneration, diseases or disorders related to inflammation, pain,and withdrawal symptoms caused by the termination of abuse of chemicalsubstances.

The compounds of the invention may also be useful as diagnostic tools ormonitoring agents in various diagnostic methods, and in particular forin vivo receptor imaging (neuroimaging), and they may be used inlabelled or unlabelled form.

In its first aspect the invention provides chemical compounds having thegeneral formula

in labelled or unlabelled form, or any of its enantiomers or any mixturethereof, or a pharmaceutically acceptable salt thereof;

wherein

represents a single or a double bond;

R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, a mono- or polycyclic aryl group, or aralkyl; and

R¹ represents a group of the formula

wherein

R² represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, amino or a fluorescent group; or

R¹ represents an mono- or polycyclic aryl group, which aryl group issubstituted one or more times with substituents selected from the groupconsisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl,methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy, aryloxy,alkylcarbonyloxy, halogen, OCF₃, CN, amino, carbamoyl, nitro, a mono- orpolycyclic aryl group, a monocyclic 5- or 6-membered, saturated,partially saturated or unsaturated heterocyclic group, and a group ofthe formula —X—R′(—Y—R″)_(n); wherein X and Y independently of eachanother represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″independently of each another represent alkyl or cycloalkyl; or afluorescent group; or

R¹ represents a monocyclic 5- or 6-membered, saturated, partiallysaturated or unsaturated heterocyclic group, which heterocyclic groupmay be substituted one or more times with substituents selected from thegroup consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl,alkynyl, methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy,aryloxy, alkylcarbonyloxy, halogen, CF₃, OCF₃, CN, sulfanyl, nitro, amono- or polycyclic aryl group, a monocyclic 5- or 6-membered,saturated, partially saturated or unsaturated heterocyclic group, and agroup of the formula —X—R′(—Y—R″)_(n); wherein X and Y independently ofeach another represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″independently of each another represent alkyl or cycloalkyl; or afluorescent group; or

R¹ represents a bi-cyclic heterocyclic group composed of a monocyclic 5-or 6-membered heterocyclic group with one heteroatom, fused to a benzenering or fused to another monocyclic 5- or 6-membered, saturated,partially saturated or unsaturated heterocyclic group, all of which issubstituted one or more times with substituents selected from the groupconsisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl,methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy, aryloxy,alkylcarbonyloxy, halogen, CF₃, OCF₃, CN, sulfanyl, amino, nitro, amono- or polycyclic aryl group, a monocyclic 5- or 6-membered,saturated, partially saturated or unsaturated heterocyclic group, and agroup of the formula —X—R′(—Y—R″)_(n); wherein X and Y independently ofeach another represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″independently of each another represent alkyl or cycloalkyl; or afluorescent group.

In a second aspect the invention provides pharmaceutical compositionscomprising a therapeutically effective amount of the chemical compoundof the invention or a pharmaceutically acceptable addition salt thereof,together with at least one pharmaceutically acceptable carrier ordiluent.

In a third aspect the invention provides an assay kit comprising thecomposition according to the invention in a unit dosage form in asuitable container.

In a fourth aspect the invention relates to a use of the chemicalcompound of the invention for the manufacture of a medicament for thetreatment or alleviation of a disease or disorder of a living animalbody, including a human, which disease or disorder is responsive to theaction of a nicotinic Acetyl Choline Receptor (nAChR) modulator.

A fifth aspect of the invention relates to the use of the chemicalcompound of the invention or any of its enantiomers or any mixturethereof, in labelled or unlabelled form, for the manufacture of adiagnostic agent for the diagnosis of a disorder or disease of a livinganimal body, including a human, which disease or disorder is responsiveto the action of a nicotinic Acetyl Choline Receptor (nAChR) modulator,or a serotonin receptor modulator.

A sixth aspect of the invention provides a method for the preparation ofthe compounds according to the invention, which method comprises

A) the step of reacting a compound having the formula

wherein R is as defined herein, with a compound of the formula R¹—Li,

wherein R¹ is as defined herein, followed by dehydration of the compoundobtained; or

B) the step of reacting a compound having the formula

wherein R is as defined herein, with a compound of formula R¹—X,

wherein R¹ is as defined herein,

and X represents halogen, boronic acid, or trialkylstannyl; or

C) the step of reducing a compound having the formula

wherein R¹ is as defined herein.

A seventh aspect of the invention provides a method of the treatment oralleviation of a disease or disorder of a living animal body, includinga human, which disease or disorder is responsive to the action of anicotinic Acetyl Choline Receptor (nAChR) modulator, which methodcomprises the step of administering to such a living animal body,including a human, in need thereof a therapeutically effective amount ofthe chemical compound of the invention

A last aspect of the invention provides a method for the non-invasivedetermination of the distribution of a tracer compound inside a whole,intact living animal or human body using a physical detection method,wherein the tracer compound is a compound according to the invention orany of its enantiomers or any mixture thereof, or a pharmaceuticallyacceptable salt thereof, in labelled or unlabelled form.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION Novel 8-azabicyclo[3.2.1]oct-2-eneand -octane Derivatives

In its first aspect the invention provides novel8-azabicyclo[3.2.1]oct-2-ene or -octane derivatives. The8-azabicyclo[3.2.1]oct-2-ene and -octane derivatives of the inventionmay be characterised by being a chemical compound of the general formula1:

in labelled or unlabelled form, or any of its enantiomers or any mixturethereof, or a pharmaceutically acceptable salt thereof;

wherein

represents a single or a double bond;

R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, a mono- or polycyclic aryl group, or aralkyl; and

R¹ represents a group of the formula

wherein R² represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, amino, or a fluorescent group; or

R¹ represents an mono- or polycyclic aryl group, which aryl group issubstituted one or more times with substituents selected from the groupconsisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl,methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy, aryloxy,alkylcarbonyloxy, halogen, OCF₃, CN, amino, carbamoyl, nitro, a mono- orpolycyclic aryl group, a monocyclic 5- or 6-membered, saturated,partially saturated or unsaturated heterocyclic group, and a group ofthe formula —X—R′(—Y—R″)_(n); wherein X and Y independently of eachanother represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″independently of each another represent alkyl or cycloalkyl; or afluorescent group; or

R¹ represents a monocyclic 5- or 6-membered, saturated, partiallysaturated or unsaturated heterocyclic group, which heterocyclic groupmay be substituted one or more times with substituents selected from thegroup consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl,alkynyl, methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy,aryloxy, alkylcarbonyloxy, halogen, CF₃, OCF₃, CN, sulfanyl, nitro, amono- or polycyclic aryl group, a monocyclic 5- or 6-membered,saturated, partially saturated or unsaturated heterocyclic group, and agroup of the formula —X—R′(—Y—R″)_(n); wherein X and Y independently ofeach another represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″independently of each another represent alkyl or cycloalkyl; or afluorescent group; or

R¹ represents a bi-cyclic heterocyclic group composed of a monocyclic 5-or 6-membered heterocyclic group with one heteroatom, fused to a benzenering or fused to another monocyclic 5- or 6-membered, saturated,partially saturated or unsaturated heterocyclic group, all of which issubstituted one or more times with substituents selected from the groupconsisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl,methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy, aryloxy,alkylcarbonyloxy, halogen, CF₃, OCF₃, CN, sulfanyl, amino, nitro, amono- or polycyclic aryl group, a monocyclic 5- or 6-membered,saturated, partially saturated or unsaturated heterocyclic group, and agroup of the formula —X—R′(—Y—R″)_(n); wherein X and Y independently ofeach another represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″independently of each another represent alkyl or cycloalkyl; or afluorescent group.

In a preferred embodiment the compound of the invention is representedby the general formula (I) wherein

R¹ represents a 1-naphthyl group, a 2-naphthyl group, a 3-naphthyl groupor a 4-naphthyl group; which naphthyl groups may be substituted one ormore times at the 5, 6, 7 or 8-positions.

In a more preferred embodiment the compound of the invention isrepresented by the general formula (I) wherein

R represents hydrogen or alkyl; and

R¹ represents a 1-naphthyl group or a 2-naphthyl group; which naphthylgroups may be substituted one or more times with substituents selectedfrom the group consisting of halogen, amino, hydroxy, alkoxy,alkoxy-alkoxy, alkoxy-alkyl, alkylcarbonyloxy, sulfanyl, alkylsulfanyl,alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl, alkylsulfanyl-alkylsulfanyl,pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl.

In a yet more preferred embodiment the compound of the invention isrepresented by the general formula (I) wherein

R¹ represents acetoxy-naphthyl, methoxy-naphthyl, hydroxy-naphthyl,bromo-naphthyl, methoxymethoxy-naphthyl, methoxyethoxy-naphthyl,ethylsulfanyl-naphthyl, methylsulfanyl-naphthyl, ethoxy-naphthyl,sulfanyl-naphthyl, methoxyethylsulfanyl-naphthyl, ethoxyethoxy-naphthyl,amino-naphthyl, dimethylamino-naphthyl, diethylamino-naphthyl,pyrrolidinyl-naphthyl, piperidinyl-naphthyl, piperazinyl-naphthyl, orhomopiperazinyl-naphthyl.

In a most preferred embodiment the compound of the invention is

(±)-3-[1-(2-Iodophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-(2-Bromophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-(2-Chlorophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-(2-iodophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-(2-bromophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-(2-chlorophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(methoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(hydroxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(2-methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

Exo-3-[6-(methoxymethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane;

(±)-3-[6-(acetyloxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-methyl-3-[6-(ethylsulfanyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-methyl-3-[6-(methylsulfanyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(ethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(sulfanyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(2-methoxyethylsulfanyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(2-ethoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-bromo-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-amino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-dimethylamino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-diethylamino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-methyl-3-[6-(N-pyrrolidinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-methyl-3-[6-(N-piperidinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-methyl-3-[6-(N-piperazinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(N-homopiperazinyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

Exo-3-[6-(2-methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-[6-methoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane;

(±)-3-[6-Isoquinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Quinolinyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Isoquinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Quinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-H-5-Benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-H-6-Benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-H-5-Benzotrizolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-H-6-Benzotrizolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-Amino-1-H-5-benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-Amino-1-H-6-benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-7-Bromo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-phthalazinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-Benzofuranyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Benzofuranyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-Benzothienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Benzothienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-Benzothiazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Benzothiazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-Methyl-5-indolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-Methyl-6-indolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-Indolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Indolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-Methyl-5-isoindolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-Methyl-6-isoindolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-Methyl-5-indazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-Methyl-6-indazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Quinolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Quinolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Cinnolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Cinnolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Quinoxalinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or

(±)-3-[7-Quinoxalinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

in their labelled or unlabelled form;

or a pharmaceutically acceptable addition salt thereof.

In another embodiment preferred embodiment the compound of the inventionrepresented by the general formula (I) wherein

R¹ represents a monocyclic 5- or 6-membered heterocyclic group, whichheterocyclic group may be un-saturated, partially un-saturated orsaturated, and may contain one or two heteroatoms selected from thegroup consisting of N, S, O and Se.

In a more preferred embodiment the compound of the invention isrepresented by the general formula (I) wherein

R¹ represents a 5-membered heterocyclic group selected from the groupconsisting of dioxolanyl, furanyl, furazanyl, imidazolyl, isoimidazolyl,isopyrrolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl,pyrrolidinyl, selenophene-yl, thiadiazolyl, thiazolyl, thienyl, andtriazolyl.

In a yet more preferred embodiment the compound of the invention isrepresented by the general formula (I) wherein

R¹ represents a 5-membered heterocyclic group selected from the groupconsisting of 2-furanyl, 2-thienyl, 4-thiazolyl, 5-imidazolyl,5-triazolyl, 2-pyrrolyl, 2-selenophene-yl, 3-thiadiazolyl, 5-isoxazolyl,5-oxazolyl, 5-pyrazolyl, 5-isothiazolyl, 5-furazanyl; which heterocyclicgroups may be substituted one or more times with substituents selectedfrom the group consisting halogen, amino, hydroxy, alkoxy,alkoxy-alkoxy, alkoxy-alkyl, sulfanyl, alkylsulfanyl,alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl, andalkylsulfanyl-alkylsulfanyl.

In an even more preferred embodiment the compound of the invention isrepresented by the general formula (I) wherein

R¹ represents a 6-membered heterocyclic group selected from the groupconsisting of dioxanyl, morpholinyl, oxazinyl, piperazinyl, piperidinyl,pyranyl, pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl.

In a still more preferred embodiment the compound of the invention isrepresented by the general formula (I) wherein

R¹ represents a 6-membered heterocyclic group selected from the groupconsisting of 3-pyridyl, 4-pyridazyl, 4-pyrimidyl, and 3-pyrazinyl;which heterocyclic groups may be substituted one or more times withsubstituents selected from the group consisting halogen, amino, hydroxy,alkoxy, alkoxy-alkoxy, alkoxy-alkyl, sulfanyl, alkylsulfanyl,alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl, andalkylsulfanyl-alkylsulfanyl.

In an even more preferred embodiment the compound of the invention isrepresented by the general formula (I) wherein

R¹ represents a bi-cyclic heterocyclic group selected from the groupconsisting of 5 or 6-benzimidazolyl, 5 or 6-benzofuranyl, 5 or6-benzothiazolyl, 5 or 6-benzothienyl, 5 or 6-benzotrizolyl, 6 or7-cinnolinyl, 5 or 6-indazolyl, 5 or 6-indolizinyl, 5 or 6-indolyl, 5 or6-isoindolyl, 6 or 7-isoquinolinyl, 6-phthalazinyl, 6 or 7-quinolinyl, 6or 7-quinolizinyl, and 6 or 7-quinoxalinyl; which heterocyclic groupsmay be substituted one or more times with substituents selected from thegroup consisting halogen, amino, hydroxy, alkoxy, alkoxy-alkyl,alkoxy-alkoxy, sulfanyl, alkylsulfanyl, alkylsulfanyl-alkoxy,alkoxy-alkylsulfanyl, and alkylsulfanyl-alkylsulfanyl.

In a most preferred embodiment the compound of the invention is

(±)-3-[2-(3-Bromofuranyl)]-8-H-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Bromofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Bromofuranyl)]-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Chlorofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Iodofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Bromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Bromothienyl)]-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Bromothienyl)]-8-H-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Iodoothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3,4-Dibromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3,4-Dichlorothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(5-Bromothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(5-Chlorothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(5-Iodothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-1-methyl-imidazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-1-methyl-imidazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-1-methyl-imidzolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Bromo-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Chloro-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Iodo-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Bromoselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Chloroselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Iodoselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(4-Bromo-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(4-Chloro-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(4-Iodo-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(2-Bromo-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(2-Chloro-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(4-Bromo-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(4-Chloro-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(3-Bromo-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(3-Chloro-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(3,6-Dibromo-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(3,6-Dichloro-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(5-Bromo-pyrimidyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(5-Chloro-pyrimidyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(2,6-dichloropyrazinyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;or

(±)-3-[3-(2-Chloro-pyrazinyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

in labelled or unlabelled form;

or a pharmaceutically acceptable addition salt thereof.

Definition of Substituents

In the context of this invention halogen represents a fluorine, achlorine, a bromine or an iodine atom.

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contain of from one to eighteen carbon atoms (C₁₋₁₈-alkyl),more preferred of from one to six carbon atoms (C₁₋₆-alkyl; loweralkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyland isohexyl. In a preferred embodiment alkyl represents a C₁₋₄-alkylgroup, including butyl, isobutyl, secondary butyl, and tertiary butyl.In a preferred embodiment of this invention alkyl represents aC₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention a cycloalkyl group designates a cyclicalkyl group, preferably containing of from three to seven carbon atoms(C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

In the context of this invention an alkenyl group designates a carbonchain containing one or more double bonds, including di-enes, tri-enesand poly-enes. In a preferred embodiment the alkenyl group of theinvention comprises of from two to six carbon atoms (C₂₋₆-alkenyl),including at least one double bond. In a most preferred embodiment thealkenyl group of the invention is ethenyl; 1,2- or 2,3-propenyl; or1,2-, 2,3-, or 3,4-butenyl.

In the context of this invention an alkynyl group designates a carbonchain containing one or more triple bonds, including di-ynes, tri-ynesand poly-ynes. In a preferred embodiment the alkynyl group of theinvention comprises of from two to six carbon atoms (C₂₋₆-alkynyl),including at least one triple bond. In its most preferred embodiment thealkynyl group of the invention is ethynyl, 1,2- or 2,3-propynyl, 1,2-,2,3- or 3,4-butynyl.

In the context of this invention a cycloalkyl-alkyl group designates acycloalkyl group as defined above, which cycloalkyl group is substitutedon an alkyl group as also defined above. Examples of preferredcycloalkyl-alkyl groups of the invention include cyclopropylmethyl andcyclopropylethyl.

In the context of this invention an alkoxy group designates an“alkyl-O-” group, wherein alkyl is as defined above.

In the context of this invention an alkoxy-alkyl group designates an“alkyl-O-alkyl-” group, wherein alkyl is as defined above.

In the context of this invention an alkoxy-alkoxy group designates an“alkyl-O-alkyl-O-” group, wherein alkyl is as defined above.

In the context of this invention an alkylsulfanyl designates an“alkyl-S-” group (a thio-alkoxy group), wherein alkyl is as definedabove. Likewise alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl, andalkylsulfanyl-alkylsulfanyl designates an alkylsulfanyl as definedabove, attached to another alkylsulfanyl or to an alkoxy group asdefined above.

In the context of this invention an alkylcarbonyloxy group designates an“alkyl-CO-O-” group, wherein alkyl is as defined above.

In the context of this invention an amino group may be a primary (—NH₂),secondary (—NH-alkyl), or tertiary (—N(alkyl)₂) amino group, i.e. it maybe substituted once or twice with an alkyl group as defined above.

In the context of this invention a mono- or polycyclic aryl groupdesignates a monocyclic or polycyclic aromatic hydrocarbon group.Examples of preferred aryl groups of the invention include phenyl,naphthyl and anthracenyl.

In the context of this invention an aralkyl group designates a mono- orpolycyclic aryl group as defined above, which aryl group is attached toan alkyl group as also defined above. A preferred aralkyl group of theinvention is benzyl.

In the context of this invention an aryloxy group designates an“aryl-O-” group, wherein aryl is a mono- or polycyclic aryl group asdefined above.

In the context of this invention a fluorescent group is a functionalgroup which can be detected by spectroscopic methods and may be selectedfrom the group of naturally occurring fluorophores or chemicallysynthesized fluorescent groups, such as rhodamine, green fluorescentprotein or fluorescein and its derivatives.

In the context of this invention a monocyclic 5- or 6-memberedheterocyclic group is a monocyclic compound holding one or moreheteroatoms in its ring structure. Preferred heteroatoms includenitrogen (N), oxygen (O), sulphur (S) and selen (Se). The ring structuremay in particular be aromatic (i.e. a heteroaryl), unsaturated orpartially unsaturated.

Examples of preferred heterocyclic aromatic monocyclic groups of theinvention include 1,3,2,4- or 1,3,4,5-dioxadiazolyl, dioxatriazinyl,dioxazinyl, 1,2,3-, 1,2,4-, 1,3,2- or 1,3,4-dioxazolyl, 1,3,2,4- or1,3,4,5-dithiadiazolyl, dithiatriazinyl, dithiazinyl, 1,2,3-dithiazolyl,2- or 3-furanyl, furazanyl, 1,2 or 4-imidazolyl, isoindazolyl,isothiazol-3,4 or 5-yl, isoxazol-3,4 or 5-yl, 1,2,3-, 1,2,4-, 1,2,5- or1,3,4-oxadiazol-3,4 or 5-yl, oxatetrazinyl, oxatriazinyl, 1,2,3,4- or1,2,3,5-oxatriazolyl, oxazol-2,4 or 5-yl, 2 or 3-pyrazinyl, 1,3 or4-pyrazolyl, 3 or 4-pyridazinyl, 2,3 or 4-pyridinyl, 2,4 or5-pyrimidinyl, 1,2 or 3-pyrrolyl (azolyl), 1,2,3,4- or2,1,3,4-tetrazolyl, thiadiazol-3,4 or 5-yl, thiazol-2,4 or 5-yl, 2 or3-thienyl, 1,2,3-, 1,2,4- or 1,3,5-triazinyl, and 1,2,3-, 1,2,4-, 2,1,3-or 4,1,2-triazolyl.

Examples of preferred saturated or partially saturated heterocyclicmonocyclic groups of the invention include 1,3,5,6,2-dioxadiazinyl,1,2,3,4,5-, 1,2,3,5,4-dioxadiazolyl, dioxanyl, 1,3-dioxolyl,1,3,5,6,2-dithiadiazinyl, 1,2,3,4,5- or 1,2,3,5,4-dithiadiazolyl,2-isoimidazolyl, isopyrrolyl, isotetrazolyl, 1,2,3- or1,2,4-isotriazolyl, morpholinyl, oxadiazinyl, 1,2,4-, 1,2,6-, 1,3,2-,1,3,6- or 1,4,2-oxazinyl, piperazinyl, homopiperazinyl, piperidinyl,1,2-, 1,3- or 1,4-pyranyl, and 1,2,3-pyrrolidinyl.

In the context of this invention a bicyclic heteroaryl group composed ofa 5 to 6 membered monocyclic heteroaryl group and a fused benzene ringor another 5 to 6 membered monocyclic heteroaryl group designates amonocyclic 5 to 6 membered heteroaryl group as defined above, whichgroup is fused to a benzene ring or fused to another 5 to 6 memberedheteroaryl group as defined above.

Examples of preferred bicyclic heteroaryl groups of the inventioninclude 3,4,5,6 or 7-anthranilyl, 2,4,5 or 6-benzimidazolyl,1,3-benzisodiazol-2,4,5,6 or 7-yl, 1,2-benzisothianin-3,4,5,6,7 or 8-yl,1,4-benzisothiazin-2,3,5,6,7 or 8-yl, 2,3,4,5,6 or 7-benzofuranyl,2,3,4,5,6,7 or 8-benzopyranyl, 1,3,2-, 1,4,2-, 2,3,1- or3,1,4-benzoxazinyl, 2,3,4,5,6 or 7-benzofuranyl, 1,3,4,5,6 or7-isobenzofuranyl, 1,2- or 1,4-benzopyranyl, 2,4,5,6 or7-benzothiazolyl, 5 or 6-benzothienyl, 5 or 6-benzotrizolyl, 2,3,4,5,6,7or 8-chromanyl, 4H-chromenyl, 3,4,5,6,7 or 8-cinnolinyl, 2,3,4,5,6 or7-indanyl, 3,4,5,6 or 7-indazolyl, 5 or 6-indolizinyl, 2,3,4,5,6 or7-indolyl, 1,3,4,5,6 or 7-isoindolyl, 2,3,4,5,6,7 or 8-quinolinyl,1,3,4,5,6,7 or 8-isoquinolinyl, 1,4,5,6,7 or 8-phthalazinyl,thieno[3.2-b]thienyl, and thieno[2.3-b]thienyl,1,4,5,6,7,8-phthalazinyl, 2,4,5,6,7,8-quinazolinyl, 6 or 7-quinolinyl, 6or 7-quinolizinyl, and 2,3,5,6,7,8-quinoxalinyl.

The compounds of the invention may be labelled or unlabelled. In theirlabelled form they may be labelled by incorporation of a isotope intothe molecule. In the context of this invention an isotope of a compoundmeans that one or more atom in the compound is substituted with anisotope of the naturally occurring atoms including deuterium, tritium,¹³C, ¹⁴C, ¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F. The isotope incorporation may bemeasured by conventional scintillation counting techniques.

Steric Isomers

The chemical compounds of the present invention may exist in (+) and (−)forms as well as in racemic forms. The racemates of these isomers andthe individual isomers themselves are within the scope of the presentinvention.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the diastereomeric saltsis by use of an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Another method forresolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or I- (tartrates, mandelates,or camphorsulphonate) salts for example.

The chemical compounds of the present invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J. Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any formsuitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride derived from hydrochloric acid, the hydrobromidederived from hydrobromic acid, the nitrate derived from nitric acid, theperchlorate derived from perchloric acid, the phosphate derived fromphosphoric acid, the sulphate derived from sulphuric acid, the formatederived from formic acid, the acetate derived from acetic acid, theaconate derived from aconitic acid, the ascorbate derived from ascorbicacid, the benzenesulfonate derived from benzensulfonic acid, thebenzoate derived from benzoic acid, the cinnamate derived from cinnamicacid, the citrate derived from citric acid, the embonate derived fromembonic acid, the enantate derived from enanthic acid, the fumaratederived from fumaric acid, the glutamate derived from glutamic acid, theglycolate derived from glycolic acid, the lactate derived from lacticacid, the maleate derived from maleic acid, the malonate derived frommalonic acid, the mandelate derived from mandelic acid, themethanesulfonate derived from methane sulphonic acid, thenaphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, thephthalate derived from phthalic acid, the salicylate derived fromsalicylic acid, the sorbate derived from sorbic acid, the stearatederived from stearic acid, the succinate derived from succinic acid, thetartrate derived from tartaric acid, the toluene-p-sulphonate derivedfrom p-toluene sulfonic acid, and the like. Such salts may be formed byprocedures well known and described in the art.

Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a chemical compound of theinvention and its pharmaceutically acceptable acid addition salt.

Metal salts of a chemical compound of the invention includes alkalimetal salts, such as the sodium salt of a chemical compound of theinvention containing a carboxy group.

The chemical compound of the invention may be provided in dissoluble orindissoluble forms together with a pharmaceutically acceptable solventssuch as water, ethanol, and the like. Dissoluble forms may also includehydrated forms such as the monohydrate, the dihydrate, the hemihydrate,the trihydrate, the tetrahydrate, and the like. In general, thedissoluble forms are considered equivalent to indissoluble forms for thepurposes of this invention.

Method of Producing the Compounds

The compounds of the invention may be prepared by any conventionalmethod useful for the preparation of analogous compounds and asdescribed in the examples below.

Starting materials for the processes described in the present patentapplication are known or can be prepared by known processes fromcommercially available materials.

A compound of the invention can be converted to another compound of theinvention using conventional methods.

In a preferred embodiment, the compounds of the invention may beprepared the following method, which method comprises:

A) the step of reacting a compound having the formula

wherein R is as defined herein, with a compound of the formula R¹—Li,

wherein R¹ is as defined herein, followed by dehydration of the compoundobtained; or

B) the step of reacting a compound having the formula

wherein R is as defined herein, with a compound of formula R¹—X,

wherein R¹ is as defined herein,

and X represents halogen, boronic acid, or trialkylstannyl; or

C) the step of reducing a compound having the formula

wherein R¹ is as defined herein.

The products of the reactions described herein are isolated byconventional means such as extraction, crystallisation, distillation,chromatography, and the like.

Biological Activity

The compounds of the present invention have proven to be nicotinicreceptor modulators. In the context of this invention the term“modulator” covers agonists, partial agonists, antagonists andallosteric modulators of the nicotinic acetyl choline receptor (nAChR).

The compounds of the present invention exhibit a nicotinic pharmacologyat least as good as nicotine itself, but preferably with lesser or evenwithout the side effects associated with the use of nicotine. Moreover,the compounds of the invention are believed to have the potential asenhancers of neurotransmitter secretion, and suppress symptomsassociated with a low activity of neurotransmitters.

The compounds of the present invention may in particular becharacterised by having one or more of the following functionalities: Ahigh binding selectivity for the receptor subtypes of neuronal nAChR's,in particular the α3 and/or the α7 subtype, binding selectivity for theserotonin receptor, a low affinity for the muscular subtype, aninduction of cell survival, an oral efficacy in vivo ofarousal/attention, a low toxicity in vivo, and by being non-mutagenic.

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or conditions as diverse as CNSrelated diseases, diseases related to smooth muscle contraction,endocrine disorders, diseases related to neurodegeneration, diseasesrelated to inflammation, pain, and withdrawal symptoms caused by thetermination of abuse of chemical substances.

In a preferred embodiment the compounds of the invention are used forthe treatment of diseases, disorders, or conditions relating to thecentral nervous system. Such diseases or disorders includes anxiety,cognitive disorders, learning deficit, memory deficits and dysfunction,Alzheimer's disease, attention deficit, attention deficit hyperactivitydisorder, Parkinson's disease, Huntington's disease, Amyotrophic LateralSclerosis, Gilles de la Tourettes syndrome, depression, mania, manicdepression, schizophrenia, obsessive compulsive disorders (OCD), panicdisorders, eating disorders such as anorexia nervosa, bulimia andobesity, narcolepsy, nociception, AIDS-dementia, senile dementia,periferic neuropathy, autism, dyslexia, tardive dyskinesia,hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia,chronic fatigue syndrome, sleeping disorders, pseudodementia, Ganser'ssyndrome, pre-menstrual syndrome, late luteal phase syndrome, chronicfatigue syndrome, mutism, trichotillomania, and jetlag.

In another preferred embodiment the compounds of the invention may beuseful for the treatment of diseases, disorders, or conditionsassociated with smooth muscle contractions, including convulsivedisorders, angina pectoris, premature labor, convulsions, diarrhoea,asthma, epilepsy, tardive dyskinesia, hyperkinesia, prematureejaculation, and erectile difficulty.

In yet another preferred embodiment the compounds of the invention maybe useful for the treatment of endocrine disorders, such asthyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

In still another preferred embodiment the compounds of the invention maybe useful for the treatment of neurodegenerative disorders, includingtransient anoxia and induced neurodegeneration.

In even another preferred embodiment the compounds of the invention maybe useful for the treatment of inflammatory diseases, disorders, orconditions, including inflammatory skin disorders such as acne androsacea, Chron's disease, inflammatory bowel disease, ulcerativecollitis, and diarrhoea.

In still another preferred embodiment the compounds of the invention maybe useful for the treatment of mild, moderate or even severe pain ofacute, chronic or recurrent character, as well as pain caused bymigraine, postoperative pain, and phantom limb pain.

Finally the compounds of the invention may be useful for the treatmentof withdrawal symptoms caused by termination of use of addictivesubstances. Such addictive substances include nicotine containingproducts such as tobacco, opioids such as heroin, cocaine and morphine,benzodiazepines and benzodiazepin-like drugs, and alcohol. Withdrawalfrom addictive substances is in general a traumatic experiencecharacterised by anxiety and frustration, anger, anxiety, difficultiesin concentrating, restlessness, decreased heart rate and increasedappetite and weight gain.

In this context “treatment” covers treatment, prevention, prophylaxisand alleviation of withdrawal symptoms and abstinence as well astreatment resulting in a voluntary diminished intake of the addictivesubstance.

Neuroimaging

The 8-azabicyclo[3.2.1]oct-2-ene and -octane derivatives of theinvention, in particular those being selective for the nicotinicreceptor subtype α3, may be useful as diagnostic tools or monitoringagents in various diagnostic methods, and in particular for in vivoreceptor imaging (neuroimaging).

In another aspect of the invention a method for the non-invasivedetermination of the distribution of a tracer compound inside a whole,intact living animal or human body using a physical detection method isprovided. According to this method a tracer compound is a compound ofthe invention, or any of its enantiomers or any mixture thereof, or apharmaceutically acceptable salt thereof, in labelled or unlabelledform.

In a preferred embodiment the physical detection method is selected fromPET, SPECT; MRS, MRI, CAT, or combinations thereof.

The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention “label” stands for thebinding of a marker to the compound of interest that will allow easyquantitative detection of said compound.

The labelled compound of the invention preferably contains at least oneradionuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this invention the radionuclideis preferably selected from ¹¹C, ¹⁸F, ¹⁵O, ¹³N, 123I, ¹²⁵I, ¹³¹I, ³H and^(99m)Tc.

An examples of commercially available labelling agents, which can beused in the preparation of the labelled compounds of the presentinvention is [¹¹C]O₂, ¹⁸F, and NaI with different isotopes of Iodine.

In particular [C¹¹]O₂ may be converted to a [¹¹C]-methylating agent,such as [¹¹C]H₃I or [¹¹C]-methyl triflate.

Labelled compounds containing e.g. [¹²⁵I] labelled 1-iodoprop-1-en-3-ylas substituent on N-8 may be prepared as described in the art [Elmaleh,et al.; J. Nucl. Med. 1996 37 1197-1202].

Labelled compounds containing e.g. [¹⁸F]-alkyl substituted N-8 may beprepared as described in the art, e.g. in WO 96/39198.

The tracer compound can be selected in accordance with the detectionmethod chosen.

In one preferred embodiment, the labelled or unlabelled compound of theinvention can be detected by a suitable spectroscopic method, inparticular UV spectroscopy and/or fluorescence spectroscopy.

In anther preferred embodiment, the compounds of the invention labelledby incorporation of a isotope into the molecule, which may in particularbe an isotope of the naturally occurring atoms including deuterium,tritium, ¹³C, ¹⁴C, ¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F, the isotope incorporationmay be measured by conventional scintillation counting techniques.

In a third preferred embodiment, the physical method for detecting saidtracer compound of the present invention is selected from PositionEmission Tomography (PET), Single Photon Imaging Computed Tomography(SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic ResonanceImaging (MRI), and Computed Axial X-ray Tomography (CAT), orcombinations thereof.

Before conducting the method of the present invention, a diagnosticallyeffective amount of a labelled or unlabelled compound of the inventionis administered to a living body, including a human.

The diagnostically effective amount of the labelled or unlabelledcompound of the invention to be administered before conducting thein-vivo method for the present invention is within a range of from 0.1ng to 100 mg per kg body weight, preferably within a range of from 1 ngto 10 mg per kg body weight.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thechemical compound of the invention.

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers and/ordiluents.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers therefor and,optionally, other therapeutic and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, nasal, topical (including buccal and sub-lingual),transdermal, vaginal or parenteral (including intramuscular,sub-cutaneous and intravenous) administration, or those in a formsuitable for administration by inhalation or insufflation.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, in the form of suppositories forrectal administration; or in the form of sterile injectable solutionsfor parenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form., obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the chemical compoundaccording to the invention may be formulated as ointments, creams orlotions, or as a transdermal patch. Ointments and creams may, forexample, be formulated with an aqueous or oily base with the addition ofsuitable thickening and/or gelling agents. Lotions may be formulatedwith an aqueous or oily base and will in general also contain one ormore emulsifying agents, stabilising agents, dispersing agents,suspending agents, thickening agents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired. It is presently contemplated that compositions containing offrom about 0.1 to about 500 mg of active ingredient per unit dosage,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

A satisfactory result can, in certain instances, be obtained at a dosageas low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The upper limit of thedosage range is about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred rangesare from about 0.001 to about 1 mg/kg i.v. and from about 0.1 to about10 mg/kg p.o.

Methods of Therapy

The compounds of the present invention are valuable nicotinic AChreceptor modulators and therefore useful for the treatment of a range ofailments involving cholinergic dysfunction as well as a range ofdisorders responsive to the action of nicotinic ACh receptor modulatorsas well as the serotonin receptor.

In another aspect the invention relates to the a method of the treatmentor alleviation of a disease, disorder or condition of a living animalbody, including a human, which disease, disorder or condition isresponsive to the action of a nicotinic Acetyl Choline Receptor (nAChR)modulator, which method comprises the step of administering to such aliving animal body, including a human, in need thereof a therapeuticallyeffective amount of the chemical compound of the invention.

In the context of this invention the term “treating” covers treatment,prevention, prophylaxis or alleviation, and the term “disease” coversillnesses, diseases, disorders and conditions related to the disease inquestion.

In a preferred embodiment the disease or disorder to be treated is adisease or disorder of the central nervous system, a disease or disordercaused by or related to smooth muscle contraction, an endocrinedisorder, a disease or disorder caused by or related toneuro-degeneration, a disease or disorder caused by or related toinflammation, pain, a withdrawal symptom caused by the termination ofabuse of chemical substances.

In a more preferred embodiment the disease or disorder of the centralnervous system is anxiety, cognitive disorders, learning deficit, memorydeficits and dysfunction, Alzheimer's disease, attention deficit,attention deficit hyperactivity disorder, Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, Gilles de laTourettes syndrome, depression, mania, manic depression, schizophrenia,obsessive compulsive disorders (OCD), panic disorders, eating disorderssuch as anorexia nervosa, bulimia and obesity, narcolepsy, nociception,AIDS-dementia, senile dementia, periferic neuropathy, autism, dyslexia,tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumaticsyndrome, social phobia, chronic fatigue syndrome, sleeping disorders,pseudodementia, Ganser's syndrome, pre-menstrual syndrome, late lutealphase syndrome, chronic fatigue syndrome, mutism, trichotillomania, andjetlag

In another preferred embodiment the disease or disorder caused by orrelated to smooth muscle contraction is convulsive disorders, anginapectoris, premature labor, convulsions, diarrhoea, asthma, epilepsy,tardive dyskinesia, hyperkinesia, premature ejaculation, and erectiledifficulty.

In a third preferred embodiment the endocrine disorder isthyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

In a fourth preferred embodiment the neuro-degenerative disease istransient anoxia and induced neurodegeneration.

In a fifth preferred embodiment the disease or disorder caused by orrelated to inflammation is an inflammatory skin disorder such as acneand rosacea, Chron's disease, inflammatory bowel disease, ulcerativecollitis, and diarrhoea.

In a sixth preferred embodiment pain is a mild, a moderate or a severepain of acute, chronic or recurrent character, a pain caused bymigraine, a postoperative pain, or a phantom limb pain.

In a third preferred embodiment the addictive substance is a nicotinecontaining product such as tobacco, an opioids such as heroin, cocaineor morphine, a benzodiazepine or a benzodiazepin-like drug, or alcohol.

It is at present contemplated that a suitable dosage lies within therange of from about 0.1 to about 500 milligram of active substancedaily, more preferred of from about 10 to about 70 milligram of activesubstance daily, administered once or twice a day, dependent as usualupon the exact mode of administration, form in which administered, theindication toward which the administration is directed, the subjectinvolved and the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

EXAMPLES

The invention is further illustrated with reference to the followingexamples which are not intended to be in any way limiting to the scopeof the invention as claimed.

Example 1 Preparatory Example

General:

All reactions involving air sensitive reagents or intermediates wereperformed under nitrogen and in anhydrous solvents. Magnesium sulfatewas used as drying agent in the workup-procedures and solvents wereevaporated under reduced pressure.

(±)-3-[6-(Methoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

To a solution of 2-Bromo-6-methoxynaphthalene (8.8 g, 37.1 mmol) intetrahydrofuran (150 ml) was added: buthyllithium (17.0 ml, 40.8 mmol)at −70° C. The mixture was stirred for 1 h at −70° C., followed byaddition of tropinone (5.2 g, 37.1 mmol) in tetrahydrofuran (75 ml). Themixture was stirred at −70° C. for 30 min, and was allowed to reach −20°C. Aqueous sodium hydroxide (200 m, 1 M) was added at −20° C., and themixture was allowed to reach room temperature. The mixture was extractedtwo times with diethyl ether (50 ml). The mixture was recrystalised frompetroleum ether and yielded the intermediate product endo andexo-3-hydroxy-3-[6-(methoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]octane.Yield 4.06 g, 37%.

A mixture of endo andexo-3-hydroxy-3-[6-(methoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane(2.50 g, 8.4 mmol), thionyl chloride (12.5 g, 105 mmol) andtetrahydrofuran (50 ml) was stirred for 30 min at 50° C. The excess ofthionyl chloride was evaporated. Potassium hydroxide (3.8 g, 67.2 mmol)and ethanol (60 ml) were added, and the mixture stirred for 20 min. Thecrude mixture was purified by chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound as free base. The corresponding salt was obtained by additionof a diethyl ether and methanol mixture (9:1), saturated with fumaricacid. Yield 2.0 g, 60%. Mp 192.6-195.4° C.

(±)-3-[6-(Hydroxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

To a solution of 2-bromo-6-methoxymethoxynaphthalene (8.3 g, 28.5 mmol)in tetrahydrofuran (100 ml) was added: buthyllithium (12.5 ml, 31.3mmol) at −70° C. The mixture was stirred for 1 h at −70° C., followed byaddition of tropinone (3.9 g, 28.5 mmol) in tetrahydrofuran (50 ml). Themixture was stirred at −70° C. for 30 min and was allowed to reach −20°C. Aqueous sodium hydroxide (75 ml, 1 M) was added at −20° C., and themixture was allowed to reach room temperature. The mixture was extractedtwo times with diethyl ether (75 ml). The mixture was triturated withpetroleum ether, and yielded the intermediate product endo andexo-3-hydroxy-3-[6-(methoxymethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane.Yield 4.9 g, 53%.

A mixture of endo andexo-3-hydroxy-3-[6-(methoxymethoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]octane(2.70 g, 7.9 mmol), thionyl chloride (11.8 g, 98.8 mmol) andtetrahydrofuran (50 ml) was stirred for 30 min at 50° C. The excess ofthionyl chloride was evaporated. Potassium hydroxide (3.5 g, 63.2 mmol)and ethanol (75 ml) were added, and the mixture stirred for 30 min. Thecrude mixture was purified by chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1), and gave thetitle compound as free base. The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1) saturated withfumaric acid. Yield 1.4 g, 60%. Mp 191.2-194.7° C.

(±)-3-[6-(2-Methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

To a solution of 2-bromo-6-(2-methoxyethoxy)naphthalene (8.0 g, 28.5mmol) in tetrahydrofuran (100 ml) was added: buthyllithium (12.5 ml,31.3 mmol) at −70° C. The mixture was stirred for 1 h at −70° C.followed by addition of tropinone (3.9 g, 28.5 mmol) in tetrahydrofuran(100 ml). The mixture was stirred at −70° C. for 30 min and was allowedto reach room temperature overnight. Aqueous sodium hydroxide (100 ml,1M) was added. The mixture was extracted two times with diethyl ether(100 ml). The crude mixture was purified by chromatography on silica gelwith dichloromethane, methanol and conc. ammonia (89:10:1), and gaveendo andexo-3-hydroxy-3-[6-(2-methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane.Yield 1.44 g, 15%.

A mixture of endo andexo-3-hydroxy-3-[6-(2-methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane(1.3 g, 3.8 mmol), thionyl chloride (5.7 g, 47.6 mmol) andtetrahydrofuran (100 ml) was stirred for 30 min at 50° C. The excess ofthionyl chloride was evaporated. Potassium hydroxide (1.7 g, 30.4 mmol)and ethanol (20 ml) were added and the mixture stirred for 20 min. Thecrude mixture was purified by chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound as free base. The corresponding salt was obtained by additionof a diethyl ether and methanol mixture (9:1) saturated with fumaricacid. Yield 0.25 g, 15%. Mp 157.3-158.9° C.

Exo-3-[6-(methoxymethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octaneFumaric Acid Salt

A mixture of endo andexo3-hydroxy-3-[6-(methoxymethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane(1.0 g, 3.1 mmol), Raney nickel (20 g, 50% in water) and ethanol (50 ml)was stirred overnight. The ethanol was separated, and the Raney nickelwas extracted two times with ethanol (25 ml). The crude mixture waspurified by chromatography on silica gel with dichloromethane, methanoland conc. ammonia (89:10:1) gave the title compound. The correspondingsalt was obtained by addition of a diethyl ether and methanol mixture(9:1) saturated with fumaric acid. Yield 20 mg, 1.5%. Mp 126.5-129.6° C.

(±)-3-[6-(Acetyloxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

A mixture of(±)-3-[6-(hydroxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene(0.49 mg, 1.8 mmol), acetic acid anhydride (1.9 g, 18 mmol) anddichloromethane (20 ml) was stirred at reflux for 1.5 h. The mixture wasevaporated and aqueous sodiumhydroxide (1 M, 50 ml) was added followedby extraction with ethyl acetate (2×25 ml). The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Yield 380 mg, 50%. Mp 154.2-155.6° C.

The following compounds are prepared likewise:

(±)-8-Methyl-3-[6-(thioethoxy)-2-naphtyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-Methyl-3-[6-(thiomethoxy)-2-naphtyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(Ethoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(Mercapto)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(2-Methoxythioethoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(2-Ethoxyethoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Bromo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Amino-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Dimethylamino-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Diethylamino-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-Methyl-3-[6-(N-pyrrolidinyl)-2-naphtyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-Methyl-3-[6-(N-piperidinyl)-2-naphtyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-8-Methyl-3-[6-(N-piperazinyl)-2-naphtyl]-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-(N-Homopiperazinyl)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

Exo-3-[6-(2-Methoxyethoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-[6-Methoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]octane;

(±)-3-[6-isoquinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Quinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Isoquinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Quinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-H-5-Benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-H-6-Benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-H-5-Benzotrizolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-H-6-Benzotrizolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-Amino-1-H-5-benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-Amino-1-H-6-benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Bromo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-phthalazinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-Benzofuranyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene

(±)-3-[6-Benzofuranyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-Benzothienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Benzothienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-Benzothiazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Benzothiazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-Methyl-5-indolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-Methyl-6-indolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-Indolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Indolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-Methyl-5-isoindolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-Methyl-6-isoindolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-Methyl-5-indazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-Methyl-6-indazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Quinolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Quinolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Cinnolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[7-Cinnolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[6-Quinoxalinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; and

(±)-3-[7-Quinoxalinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene.

Method A(±)-3-[2-(3-Bromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene FumaricAcid Salt

To a solution of 3-bromothiophene (25.0 g, 153.3 mmol) in THF (250 ml)was added lithiumdiisopropylamide (2 M, 168.7 mmol) at −80° C. Themixture was stirred for 1 h at −80° C. followed by addition of tropinone(21.3 g, 153.3 mmol) in THF (200 ml). The mixture was stirred at −80° C.for 1 h and was allowed to reach room temperature overnight. Sodiumhydroxide (1 M, 200 ml) was added and extracted three times withdiethylether (300 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave theintermediate endo andexo-3-[3-bromo-(2-thienyl)]-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane.Yield 8.90 g, 19%.

A mixture of endo andexo-3-[3-bromo-(2-thienyl)]-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane(8.85 g, 29.3 mmol) and concentrated hydrochloric acid (100 ml) wasstirred for 2 h. The hydrochloric acid was evaporated and sodiumhydroxide (1 M, 200 ml) was added and the mixture was extracted twicewith ethyl acetate (2×100 ml). Yield 8.3 g, 100%. The corresponding saltwas obtained by addition of a diethyl ether and methanol mixture (9:1),saturated with fumaric acid. Mp 130-132° C.

(±)-3-[2-(3-Bromofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene fumaricacid salt

Was prepared according to method A. Mp 150.3-153.0° C.

Method B (±)-3-[2-(3-Bromothienyl)]-8-H-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

To a mixture of(±)-3-[2-(3-bromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (4.0 g,14.1 mmol) and anhydrous xylene (40 ml) was added:2-chloroethylchloroformate (3.02 g, 21.1 mmol) at 0° C. The mixture wasstirred at reflux for 2 days. Methanol (50 ml) was added and the mixturewas heated at reflux for 2 h. The methanol was evaporated and sodiumhydroxide (60 ml, 1 M) was added. The mixture was extracted with ethylacetate (2×50 ml). The crude mixture was purified by chromatography onsilica gel with dichloromethane, methanol and conc. ammonia (89:10:1)gave the title compound. Yield 2.96 g, 78%. The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Mp 184-186° C.

(±)-3-[2-(3-Bromofuranyl)]-8-H-8-azabicyclo[3.2.1]oct-2-ene fumaric acidsalt

Was prepared according to method B. Mp 176.1-176.9° C.

Method C (±)-3-[2-(3-Bromothienyl)]-8-ethyl-8-azabicyclo[3.2.1]oct-2-eneFumaric Acid Salt

A mixture of (±)-3-[2-(3-bromothienyl)]-8-H-8-azabicyclo[3.2.1]oct-2-ene(0.70 g, 2.6 mmol), bromoethane (339 mg, 3.1 mmol),diisopropylethylamine (335 mg, 2.6 mmol) and dimethylformamide (20 ml)was stirred at 80° C. for 4 h. Sodium hydroxide (40 ml, 1 M) was addedand the mixture was extracted with ethyl acetate (2×40 ml). The crudemixture was purified by chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound. Yield 0.57 g (73%). The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1) saturated withfumaric acid. Mp 136-138° C.

(±)-3-[2-(3-Bromofuranyl)]-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene FumaricAcid Salt

Was prepared according to method C. Mp 139-141.2° C.

The following compounds are prepared likewise:

(±)-3-[2-(3-Iodoothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Chlorofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Iodofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-(2-Iodophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-(2-Bromophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[1-(2-Chlorophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3,4-Dibromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3,4-Dichlorothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(5-Bromothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(5-Chlorothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(5-Iodothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-1-methyl-imidazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-1-methyl-imidazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-1-methyl-imidzolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Bromo-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Chloro-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Iodo-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Bromoselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Chloroselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[2-(3-Iodoselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(4-Bromo-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(4-Chloro-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(4-Iodo-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Bromo-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Chloro-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[5-(4-Iodo-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(2-Bromo-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(2-Chloro-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(4-Bromo-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(4-Chloro-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(3-Bromo-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(3-Chloro-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(3,6-Dibromo-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(3,6-Dichloro-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(5-Bromo-pyrimidyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[4-(5-Chloro-pyrimidyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

(±)-3-[3-(2,6-dichloropyrazinyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;and

(±)-3-[3-(2-Chloro-pyrazinyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene.

Intermediate Preparations 2-Bromo-6-methoxynaphthalene

Sodium hydride (60%, 4.5 g, 112 mmol) was added in small portions to amixture of 6-bromo-2-naphthol (25.0 g, 112 mmol), iodomethane (11.8 g,168 mmol) and dimethylsulfoxide (150 ml). The mixture was stirred atroom temperature overnight. Sodium hydroxide (200 ml, 1 M) was added,and the mixture was filtered. Yield 25.1 g, 95%. Mp 76-82° C.

2-Bromo-6-methoxymethoxynaphthalene

Sodium hydride (60%, 4.5 g, 112 mmol) was added in small portions to amixture of 6-bromo-2-naphthol (25.0 g, 112 mmol), bromomethylmethylether(21.0 g, 168 mmol) and dimethylformamide (150 ml). The mixture wasstirred at room temperature for 1 h. Sodium hydroxide (200 ml, 1 M) wasadded and the mixture was extracted with diethyl ether. The product waspurified chromatographically, using dichloromethane as solvent. Yield15.7 g, 52%. Mp 46.8-49.2° C.

2-Bromo-6-methoxyethoxynaphthol

Sodium hydride (60%, 5.3 g, 134 mmol) was added in small portions to amixture of 6-bromo-2-naphthol (25.0 g, 112 mmol),2-bromoethylmethylether (17.1 g, 123 mmol) and dimethylformamide (150ml). The mixture was stirred at room temperature for 5 h. Aqueous sodiumhydroxide (200 ml, 1 M) was added, and the mixture was allowed to stirovernight. The crystals were filtered. Yield 28.2 g, 89%. Mp 54-55° C.

Example 2 Biological Activity

The affinity of compounds of the invention for nicotinic ACh receptorshave been investigated in three test for in vitro inhibition of³H-epibatidin binding, ³H-α-bungarotoxin binding and ³H-cytisine bindingas described below.

In Vitro Inhibition of ³H-Cytisine Binding

The predominant subtype with high affinity for nicotine is comprised ofα₄ and β₂ subunits. nAChRs of the latter type can selectively belabelled by the nicotinic ACh modulator ³H-cytisine.

Tissue Preparation:

Preparations are performed at 0-4° C. Cerebral corticies from maleWistar rats (150-250 g) are homogenised for 20 sec in 15 ml Tris, HCl(50 mM, pH 7.4) containing 120 mM NaCl, 5 mM KCl, 1 mM MgCl₂ and 2.5 mMCaCl₂ using an Ultra-Turrax homogeniser. The homogenate is centrifugedat 27,000×g for 10 min. The supernatant is discarded and the pellet isresuspended in fresh buffer and centrifuged a second time. The finalpellet is resuspended in fresh buffer (35 ml per g of original tissue)and used for binding assays.

Assay:

Aliquots of 500 μl homogenate are added to 25 μl of test solution and 25μl of ³H-cytisine (1 nM, final concentration), mixed and incubated for90 min at 2° C. Non-specific binding is determined using (−)-nicotine(100 μM, final concentration). After incubation the samples are added 5ml of ice-cold buffer and poured directly onto Whatman GF/C glass fibrefilters under suction and immediately washed with 2×5 ml ice-coldbuffer. The amount of radioactivity on the filters is determined byconventional liquid scintillation counting. Specific binding is totalbinding minus non-specific binding.

In Vitro Inhibition of ³H-α-Bungarotoxin Binding Rat Brain

α-Bungarotoxin is a peptide isolated from the venom of the Elapidaesnake Bungarus multicinctus (Mebs et al., Biochem. Biophys. Res.Commun., 44(3), 711 (1971)) and has high affinity for neuronal andneuromuscular nicotinic receptors, where it acts as a potent antagonist.³H-α-Bungarotoxin binds to a single site in rat brain with an uniquedistribution pattern in rat brain (Clarke et al., J. Neurosci. 5,1307-1315 (1985)).

³H-α-Bungarotoxin labels nAChR formed by the α₇ subunit isoform found inbrain and the α₁ isoform in the neuromuscular junction (Changeaux, FidiaRes. Found. Neurosci. Found. Lect. 4, 21-168 (1990). Functionally, theα₇ homo-oligomer expressed in oocytes has a calcium permeability greaterthan neuromuscular receptors and, in some instances greater than NMDAchannels (Seguela et al., J. Neurosci. 13, 596-604 (1993).

Tissue preparation:

Preparations are performed at 0-4° C. Cerebral cortices from male Wistarrats (150-250 g) are homogenised for 10 sec in 15 ml 20 mM Hepes buffercontaining 118 mM NaCl, 4.8 mM KCl, 1.2 mM MgSO₄ and 2.5 mM CaCl₂ (pH7.5) using an Ultra-Turrax homogeniser. The tissue suspension iscentrifuged at 27,000×g for 10 min. The supernatant is discarded and thepellet is washed twice by centrifugation at 27,000×g for 10 min in 20 mlfresh buffer, and the final pellet is resuspended in fresh buffercontaining 0.01% BSA (35 ml per g of original tissue) and used forbinding assays.

Assay:

Aliquots of 500 μl homogenate are added to 25 μl of test solution and 25μl of ³H-α-bungarotoxin (2 nM, final concentration), mixed and incubatedfor 2 h at 37° C. Non-specific binding is determined using (−)-nicotine(1 mM, final concentration). After incubation the samples are added 5 mlof ice-cold Hepes buffer containing 0.05% PEI and poured directly ontoWhatman GF/C glass fibre filters (presoaked in 0.1% PEI for at least 6h) under suction and immediately washed with 2×5 ml ice-cold buffer. Theamount of radioactivity on the filters is determined by conventionalliquid scintillation counting. Specific binding is total binding minusnon-specific binding.

In Vitro Inhibition of ³H-Epibatidin Binding

Epibatidin is an alkaloid that was first isolated from the skin of theEcuadoran frog Epipedobates tricolor and was found to have very highaffinity for neuronal nicotinic receptors, where it acts as a potentagonist. ³H-epibatidin binds to two sites in rat brain, both of whichhave pharmacological profiles consistent with neuronal nicotinicreceptors and a similar brain regional distribution (Hougling et al.,Mol. Pharmacol. 48, 280-287 (1995)).

The high affinity binding site for ³H-epibatidin is most certainlybinding to the α₄β₂ subtype of nicotinic receptors. The identity of thelow affinity site is still unknown; does it represent a second nicotinicreceptor or a second site in the same receptor. The inability ofα-bungarotoxin to compete for ³H-epibatidin binding sites indicates thatneither site measured represents the nicotinic receptor composed of α₇subunits.

Tissue preparation:

Preparations are performed at 0-4° C. The forebrain (÷cerebellum) from amale Wistar rat (150-250 g) is homogenised for 10-20 sec in 20 ml Tris,HCl (50 mM, pH 7.4) using an Ultra-Turrax homogeniser. The tissuesuspension is centrifuged at 27,000×g for 10 min. The supernatant isdiscarded and the pellet is washed three times by centrifugation at27,000×g for 10 min in 20 ml fresh buffer, and the final pellet isresuspended in fresh buffer (400 ml per g of original tissue) and usedfor binding assays.

Assay:

Aliquots of 2.0 ml homogenate are added to 0.100 ml of test solution and0.100 ml of ³H-epibatidin (0.3 nM, final concentration), mixed andincubated for 60 min at room temperature. Non-specific binding isdetermined using (−)-nicotine (30 μM, final concentration). Afterincubation the samples are poured directly onto Whatman GF/C glass fibrefilters (presoaked in 0.1% PEI for at least 20 min) under suction andimmediately washed with 2×5 ml ice-cold buffer. The amount ofradioactivity on the filters is determined by conventional liquidscintillation counting. Specific binding is total binding minusnon-specific binding.

Results are given as IC₅₀ values; the concentration (μM) that inhibitbinding of the radioactive ligand by 50%.

What is claimed is:
 1. An 8-azabicyclo[3.2.1]oct-2-ene compound havingthe general formula

in labelled or unlabelled form, or any of its enantiomers or any mixturethereof, or a pharmaceutically acceptable salt thereof; wherein Rrepresents hydrogen, alkyl, or cycloalkylalkyl; and R′ represents anaphthyl group, which is substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy,alkylcarbonyloxy, halogen, OCF₃, CN, amino, carbamoyl, nitro,pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, sulfanyl,alkylsulfanyl, alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl andalkylsufanyl-alkylsufanyl.
 2. The 8-azabicyclo[3.2.1]oct-2-ene compoundof claim 1, wherein R¹ represents a 1-naphthyl group, a 2-naphthylgroup, a 3-naphthyl group or a 4-naphthyl group; which naphthyl groupsare substituted one or more times at the 5, 6, 7 or 8-positions.
 3. The8-azabicyclo[3.2.1]oct-2-ene compound of claim 2, wherein R representshydrogen or alkyl; and R¹ represents a 1-naphthyl group or a 2-naphthylgroup; which naphthyl groups are substituted one or more times withsubstituents selected from the group consisting of halogen, amino,hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy, alkylcarbonyloxy,sulfanyl, alkylsulfanyl, alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl,alkylsulfanyl-alkylsulfanyl, pyrrolidinyl, piperidinyl, piperazinyl, andhomopiperazinyl.
 4. The 8-azabicyclo[3.2.l]oct-2-ene compound of claim3, wherein R¹ represents acetoxy-naphthyl, methoxy-naphthyl,hydroxy-naphthyl, bromo-naphthyl, methoxymethoxy-naphthyl,methoxyethoxy-naphthyl, ethylsulfanyl-naphthyl, methylsulfanyl-naphthyl,ethoxy-naphthyl, sulfanyl-naphthyl, methoxyethylsulfanyl-naphthyl,ethoxyethoxy-naphthyl, amino-naphthyl, dimethylamino-naphthyl,diethylamino-naphthyl, pyrrolidinyl-naphthyl, piperidinyl-naphthyl,piperazinyl-naphthyl, or homopiperazinyl-naphthyl.
 5. The8-azabicyclo[3.2.1]oct-2-ene of claim 1 which is(±)-3-[6-(methoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(hydroxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(2-methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(acetyloxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-8-methyl-3-[6-(ethylsulfanyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;(±)-8-methyl-3-[6-(methylsulfanyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(ethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(sulfanyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(2-methoxyethylsulfanyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(2-ethoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-bromo-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-amino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-dimethylamino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-diethylamino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-8-methyl-3-[6-(N-pyrrolidinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;(±)-8-methyl-3-[6-(N-piperidinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;(±)-8-methyl-3-[6-(N-piperazinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(N-homopiperazinyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[7-Bromo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[7-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[7-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or(±)-3-[7-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or apharmaceutically acceptable addition salt thereof.
 6. A pharmaceuticalcomposition comprising a therapeutically effective amount of the8-azabicyclo[3.2.1]oct-2-ene compound of claim 1, or a pharmaceuticallyacceptable addition salt thereof, together with at least onepharmaceutically acceptable carrier or diluent.
 7. A method for thepreparation of the 8-azabicyclo[3.2.1]oct-2-ene compound according toclaim 1, which method comprises the step of reacting a compound havingthe formula

wherein R is as defined in claim 1, with a compound of formula R¹—X,wherein R¹ is as defined in claim 1, and X represents halogen, boronicacid, or trialkylstannyl; or the step of reducing a compound having theformula

wherein R¹ is as defined in claim 1.